The central tenet of this application for extension of a MERIT award is that the ability of the mammalian brain to undergo plastic changes in the behavior of neural circuits via long-lasting changes in synaptic transmission is of fundamental importance for virtually all aspects of nervous system function including learning and memory. Among the best models for such changes are NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). Although significant progress has been made in the understanding of the molecular mechanisms underlying these forms of synaptic plasticity, much remains unknown. Using a combination of electrophysiological and molecular techniques the specific aims of this proposal will cover a range of topics related to the mechanisms of synaptic plasticity in the hippocampus. Specific aim 1 will examine the roles of the postsynaptic scaffolding proteins PSD95 and SAP97 in controlling basal synaptic transmission as well as LTP and LTD. Specific aim 2 will examine the effects of activation of the transcription factor CREB on synaptic function and plasticity. Both of these aims will involve using viral mediated gene transfer to express recombinant proteins in neurons from which electro- physiological recordings will be made. Specific aim 3 will examine the detailed mechanisms underlying LTD of NMDA receptor-medatied synaptic responses focusing on the role of protein phosphatases and receptor endocytosis. Specific aim 4 will examine the role of the cytokine TNFa in influencing synaptic function and plasticity. These experiments will provide fundamental information about the molecular mechanisms by which excitatory synapses can be modified by activity. Such information may eventually lead to the development of pharmacological agents that modify synaptictransmissionin ways that promote cognitive function, alleviate psychiatric symptoms or prevent the inevitable deterioration of cognitive function that occurs during illness and aging.